Biomedical subjects

Mitsugu Sekimoto

Publications and source records attributed to Mitsugu Sekimoto.

At least 19 recordsLinked to original sources

PubMed2007

Castleman's disease of the rectum: report of a case.

Gastrointestinal Castleman's disease is very rare. We report the case of a 52-year-old patient with asymptomatic rectal polyp, which was diagnosed as Castleman's disease. The rectal polyp was identified during preoperative workup of gastric adenocarcinoma. The rectal polyp was 4-cm long with a short, thick stalk. Pathologic examination of the resected polyp showed lymph follicle hyperplasia with remarkable lymphocyte and plasma cell infiltration in the submucosal area, consistent with plasma cell type of Castleman's disease. This is the first report of Castleman's disease of the rectum concomitant with gastric adenocarcinoma. A literature review of Castleman's disease identified only five cases of gastrointestinal Castleman's disease, and all five cases were of the hyaline vascular type. A high index of suspicion of this disease is important for preoperative diagnosis.

Adenocarcinoma↗

PubMed2007

Total splenic vein thrombosis after laparoscopic splenectomy: a possible candidate for treatment.

BACKGROUND: Portal or splenic vein thrombosis (PSVT) is a common disorder after laparoscopic splenectomy (LS). Splenomegaly is a well-known risk factor for PSVT. However, no treatment strategy for PSVT has been established. METHODS: Thirty-three consecutive patients who had undergone LS and postoperative imaging surveillance were examined. PSVT was classified according to the site of thrombosis. We evaluated patient background, operative factors, and clinical symptoms. RESULTS: Spleen weight of patients with PSVT (n = 17, median 218 g) was greater than that of patients without PSVT (n = 16, median 101 g). Seven patients developed thrombosis involving the entire splenic vein (total splenic vein thrombosis), and 4 of them had clinical symptoms (fever >38 degrees C and/or abdominal pain). The incidence of clinical symptoms was significantly more frequent in patients with than without total SVT. Operation time, blood loss, and spleen weight were also significantly greater in patients with total SVT. Multiple logistic regression analysis demonstrated spleen weight was the strongest predictor of PSVT and total SVT. CONCLUSION: Patients with total SVT have greater risk factors for PSVT and frequently have clinical symptoms. They are candidates for anticoagulation therapy.

Adolescent↗

PubMed2007

The gene expression profile represents the molecular nature of liver metastasis in colorectal cancer.

The major cause of death in colorectal cancer is related to liver metastasis. Although the metastatic process has been well studied, many aspects of the molecular genetic basis of metastasis remain unclear. Elucidation of the molecular nature of liver metastasis is urgent to improve the outcome of colorectal cancer. We analyzed the chronological gene expression profiles of 104 colorectal samples corresponding to oncogenic development including normal mucosa, localized and metastasized primary tumors, and liver metastatic lesions as fundamental samples using a custom cDNA microarray. The gene expression patterns in 104 samples were classified into four groups closely associated with their metastatic status, and the genes of each group appropriately reflected the metastatic process. To investigate the existence of metastatic potential in primary tumors using metastasis-related genes detected by chronological analysis, we performed a hierarchical cluster and supervised classification analysis of 28 independent primary tumors. Hierarchical cluster analysis segregated the tumors according to their final metastatic status, rather than their clinical stages, and the profile of metastasized primary tumors resembled one of a metastatic lesion apart from a primary lesion rather than one of a non-metastasized primary tumor. Using the supervised classification approach, the expression profile of these genes allowed the classification of tumors diagnosed as localized cancer into two classes, the localized and the metastasized class, according to their final metastatic status. The disease-free survival and overall survival were significantly longer in the localized class than the metastasized class. Chronological analysis of the gene expression profile provides a better understanding of the metastatic process. Our results suggest that the metastatic potential is already encoded in the primary tumor and is detectable by a gene expression profile, which allows the prediction of liver metastasis in patients diagnosed with localized tumors and also the design of new strategies for the treatment and diagnosis of colorectal cancer.

Aged↗

PubMed2006

Complete response of highly advanced colon cancer with multiple lymph node metastases to irinotecan combined with UFT: report of a case.

Massive lymph node metastasis of the para-aortic region and supraclavicular lymph nodes, Virchow's lymph node metastasis due to colon cancer, is extremely rare. We herein report a case of such systemic lymph node metastasis that was successfully treated with a combination of irinotecan (CPT-11) and UFT, a combination drug of tegafur and uracil. The patient was a 57-year-old woman who had a tumor in the ascending colon, and massively swollen para-aortic and supraclavicular lymph node metastasis. She was treated with combination chemotherapy of CPT-11 and UFT. The main tumor was detected as a decompressed scar, and the supraclavicular and para-aortic lymph nodes had completely disappeared after the second cycle of treatment. A histopathological examination and immunohistochemistry with cytokeratin showed complete remission of adenocarcinoma in the tumor and para-aortic lymph nodes. She remains alive without recurrence 52 months after chemotherapy. Combination chemotherapy of CPT-11 and UFT may be of potential value in the treatment of advanced colorectal carcinoma, and both histopathological and immunohistochemical confirmation of a complete remission may indicate prolonged disease-free survival.

Adenocarcinoma↗

PubMed2006

Preliminary results of phase I trial of oral uracil/tegafur (UFT), leucovorin plus irinotecan and radiation therapy for patients with locally recurrent rectal cancer.

BACKGROUND: Surgical attempts for locally recurrent rectal cancer often fail due to local re-recurrence and distant metastasis. Preoperative chemoradiation may enhance better local control and survival. The aim of this study was to assess the safety of oral uracil and tegafur (UFT) plus leucovorin (LV), and irinotecan combined with radiation and determine the maximum-tolerated dose (MTD) and dose limiting toxicity (DLT) of the triple drug regimen. PATIENTS AND METHODS: Patients with locally recurrent rectal cancer received escalating doses of irinotecan on days 1, 8, 15, and 22 (starting at 30 mg/m2, with 10 mg increments between consecutive cohorts) and fixed doses of UFT (300 mg/m2) plus LV (75 mg/day) on days 3 to 7, 10 to 14, 17 to 21, and 24 to 28. Radiation was given 5 days per week totaling 40 to 50 Gy (2Gy/day). RESULTS: Six patients were treated at the starting dose, and 2 received the full scheduled chemoradiotherapy. The other 4 patients had grade 3 diarrhea and diarrhea was the DLT. One patient had partial response and he had subsequently radical surgical resection. Median progression free survival for local recurrence was 320 days. CONCLUSION: Irinotecan plus UFT/LV with concomitant radiotherapy in patients with locally recurrent rectal cancer was not feasible due to diarrhea in this setting. Modification of the treatment is needed.

Journal Article↗

PubMed2006

Correlation of GLUT-1 overexpression, tumor size, and depth of invasion with 18F-2-fluoro-2-deoxy-D-glucose uptake by positron emission tomography in colorectal cancer.

We investigated the wide variability of 18F-2-fluoro-2-deoxy-D: -glucose (FDG) uptake, semiquantified as standardized uptake value (SUV), in positron emission tomography (PET) scanning, in 20 patients with colorectal cancer (CRC), including 1 with synchronous hepatic metastasis. The sensitivity of PET in CRC diagnosis was 100%, with a mean SUV of 8.0 (3.1-11.9). Tumor size and depth of invasion were associated with higher SUVs (P=.0004, .042, respectively). Strong glucose transporter-1 (GLUT-1) expression had significantly positive correlation with the SUV (r=.619, P=.003). GLUT-1 expression revealed positive staining in 17 (85%) of the 20 primary lesions. The central part of the tumor, thought to be relatively hypoxic, had stronger GLUT-1 expression and a higher SUV than the periphery, in both the primary tumor and hepatic metastatic foci. Our data suggest that the SUVs of FDG uptake in PET may be a noninvasive biomarker for advanced CRC, indicative of a large hypoxic tumor with deep invasion.

Adenocarcinoma↗

PubMed2006

Low-dose oxaliplatin enhances the antitumor efficacy of paclitaxel in human gastric cancer cell lines.

BACKGROUND: The enhanced antitumor effect of paclitaxel when used with oxaliplatin in gastric cancer is reported, however the underlying biological mechanism is unknown. METHODS: We tested the cytotoxic activity, apoptosis, and mitotic catastrophe of paclitaxel and oxaliplatin in MKN-28 and MKN-45 gastric cancer cell lines. The modulation of survivin expression was determined by Western blotting. RESULTS: WST-1 assay indicated that paclitaxel plus oxaliplatin showed better cytotoxicity than paclitaxel alone, even when low concentrations of oxaliplatin were used. Flow cytometry analysis revealed significantly greater increases in apoptotic cells after treatment with paclitaxel followed by low-dose oxaliplatin (1 microM) than after any single-reagent regimen in the MKN-45 cell line. In MKN-28, a difference existed only between combination treatment and oxaliplatin treatment. Morphologic examination showed that the cells undergoing mitotic catastrophe were highest in the combination groups in the both cell lines. Downregulation of survivin expression was found by Western blotting with treatment by paclitaxel, oxaliplatin, or their combination. CONCLUSION: Our findings suggest that the mechanism of enhanced cytotoxicity might be through enhanced mitotic catastrophe and apoptosis, which is possibly due to chemotherapy-induced downregulation of surviving. The combination of paclitaxel and low-dose oxaliplatin should be incorporated into the design of a clinical trial.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Single-photon emission computed tomography in the screening for postoperative pulmonary embolism.

The aim of the study was to evaluate the usefulness of serial lung perfusion scintigraphy prospectively using single-photon emission computed tomographic image (SPECT) in screening for pulmonary embolism (PE) after elective surgery for gastrointestinal malignancy. PE was examined pre- and postoperatively with SPECT. Diagnosis of PE was based on segmental perfusion defect visualization in at least two of three planes on a SPECT image compared with preoperative SPECT images. Final diagnosis was determined by detection of embolus with multidetector helical CT (MDCT). No perioperative anticoagulant was used. Thirty-four patients were enrolled. One patient was excluded because of thrombophilia. In preoperative scans, nonsegmental defects were detected in 11 and a segmental defect in 1 patient, who was then diagnosed as PE preoperatively. Among 21 patients with normal preoperative SPECT, 2 had nonsegmental and 5 had segmental defects postoperatively. Among 11 patients with nonsegmental preoperative SPECT, 7 had nonsegmental and 4 had segmental defects postoperatively. Postoperative segmental defects were differentiated by their shape only and there was no need to compare pre- and postoperative SPECT. MDCT confirmed four patients with PE among nine with segmental defects postoperatively. Our results of screening for PE by visualization at least two planes of SPECT images suggest that postoperative SPECT scan is suitable for the diagnosis of postoperative PE.

Aged↗

PubMed2006

Antisense to cyclin D1 inhibits vascular endothelial growth factor-stimulated growth of vascular endothelial cells: implication of tumor vascularization.

PURPOSE: Our aim was to determine the effects of cyclin D1 inhibition on tumor-associated neovascularization and endothelial cell growth. EXPERIMENTAL DESIGN: We have generated adenovirus system for antisense to cyclin D1 (AS CyD1) and evaluated in vitro and in vivo effects. Small interfering RNA against cyclin D1 was also used to analyze cyclin D1 inhibition-associated vascular endothelial growth factor (VEGF) regulation. RESULTS: The xenografts treated with adenoviral AS CyD1 showed less vessel density and displayed smaller tumor size in colon cancer cell lines HCT116 and DLD1. In vitro studies indicated that AS CyD1 decreased VEGF protein expression in DLD1 but not in HCT116. Cyclin D1 small interfering RNA caused a decrease in VEGF expression at protein and RNA levels in DLD1. A modest decrease was noted in the VEGF promoter activity, with inactivation of the STAT3 transcription factor through dephosphorylation. On the hand, the cyclin D1 inhibition plus STAT3 inhibitor markedly decreased VEGF expression in HCT116, although VEGF did not change by the STAT3 inhibitor alone. In cultures of human umbilical vein endothelial cells (HUVEC), VEGF augmented cyclin D1 expression and cell growth. AS CyD1 significantly inhibited HUVEC growth even in the presence of VEGF. AS CyD1 also significantly suppressed in vitro tube formation in VEGF-treated HUVEC and in vivo macroaneurysm formation in VEGF-treated Matrigel plug. CONCLUSIONS: Our results suggest that cyclin D1 may play a role in the maintenance of VEGF expression and that AS CyD1 could be potentially useful for targeting both cancer cells and their microenvironment of tumor vessels.

Animals↗

PubMed2006

Construction of a novel DNA decoy that inhibits the oncogenic beta-catenin/T-cell factor pathway.

The oncogenic beta-catenin/T-cell factor (TCF) signal is a common trigger inducing expressions of various cancer-related genes and is activated in various types of human malignancy. The aim of this study was to create an effective double-stranded DNA decoy that would interfere with endogenous TCF hyperactivity in tumor cells. We first established the TCF-activated model using nontumor human embryonic kidney 293 (HEK293) cells by introducing a beta-catenin cDNA. Based on a consensus TCF-binding sequence in the cyclin D1 and c-myc promoters, several double-stranded oligodeoxynucleotides were designed and tested for their ability to inhibit TCF activity in the HEK293 model. Among them, the 18-mer oligodeoxynucleotide stably formed double-stranded DNA and efficiently inhibited TCF activity. FITC-labeled oligodeoxynucleotide was efficiently incorporated into the nucleus at 6 hours and remained within cells for up to 72 to 96 hours. When compared with scrambled oligodeoxynucleotide, we found that the 18-mer TCF decoy significantly inhibited TCF activity and promoter activities of the downstream target genes, such as cyclin D1, c-myc, and matrix metalloproteinase 7 in HCT116 colon cancer cells. Reverse transcription-PCR assays indicated that mRNA expression of these genes decreased with treatment of the TCF decoy. Proliferation assay showed that the TCF decoy significantly inhibited growth of HCT116 tumor cells, but not of nontumor HEK293 cells. Our data provide evidence that the TCF decoy reduced both TCF activity and transcriptional activation of downstream target genes. Thus, this TCF decoy is potentially an efficient and nontoxic molecular targeting therapy for controlling malignant properties of cancer cells.

Base Pair Mismatch↗

PubMed2006

Hypoxia-induced up-regulation of angiopoietin-2 in colorectal cancer.

Angiogenesis is a compensatory mechanism that enables malignant tumors to survive in an oxygen-deficient environment. To test our hypothesis that hypoxia stimulates the production of angiopoietin-2 (Ang-2) in colorectal cancer (CRC), we investigated the expression of Ang-2 in three cultured CRC cell lines, and in specimens from 11 CRC metastatic liver tumors. Hypoxia-induced Ang-2 mRNA expression was clearly evident in HCT116 cells that did not express Ang-2 under normoxic conditions. Ang-2 mRNA was detected only after 48 h in hypoxic serum-deprived cultures in a LoVo cell line, and under both normoxic and hypoxic conditions without any noticeable difference in the HT29 cells. There was a stepwise increase in Ang-2 expression from the periphery to the central part of the liver metastatic foci, whereas an inverse result was noted in tumor blood vessels, with a gradual decrease in CD31-positive ECs from the edge to the central region of the metastatic lesion. An expression pattern similar to Ang-2 was found in glucose transporter 1 (Glut-1), a known hypoxia-induced factor. These findings suggest that hypoxia plays an important role in inducing the expression of Ang-2 in CRC.

Angiopoietin-2↗

PubMed2006

Expression of type I interferon receptor as a predictor of clinical response to interferon-alpha therapy of gastrointestinal cancers.

Interferon (IFN) is used in the treatment of many malignancies and viral disorders. We recently reported a significant correlation between the efficacy of IFN-alpha combined with chemotherapy in the treatment of advanced hepatocellular carcinoma (HCC) and IFN-alpha/type I IFN receptor (IFNAR2) expression. It is possible that the expression of IFNAR2 in gastrointestinal cancerous tissue, apart from HCC, may predict the efficacy of IFN-alpha combination therapy. We investigated the expression of IFNAR2 in 100 gastrointestinal cancerous tissues. IFNAR2 expression was examined using immunohistochemistry, in surgically resected tissue samples (20 esophageal, 20 gastric, 20 colorectal, 20 cholangiocarcinoma, and 20 pancreatic samples). The expression rate of IFNAR2 was 35.0% (7/20), 25.0% (5/20), 20.0% (4/20), 45.0% (9/20), and 25.0% (5/20) in esophageal, gastric cancer, colorectal, cholangiocarcinoma and pancreatic cancer samples, respectively. In our previous report, the expression rate of IFNAR2 in HCC samples was 64.8% (59/91). Thus, the expression rates of IFNAR2 in the five types of gastrointestinal cancers tested here were low, compared with HCC. The clinical efficacy of IFN-alpha mono- or combination therapies in patients with gastrointestinal neoplasms is expected to be lower than in patients with HCC based on the expression level of IFNAR2.

Gastrointestinal Neoplasms↗

PubMed2005

Oxaliplatin, a potent inhibitor of survivin, enhances paclitaxel-induced apoptosis and mitotic catastrophe in colon cancer cells.

BACKGROUND: Clinical studies have demonstrated that oxaliplatin, a novel platinum derivative, is a potent chemotherapeutic agent, especially when combined with other reagents. The aim of the present study was to explore the mechanism of such action. METHODS: Using colon cancer cell lines, we examined changes in cell cycle, apoptosis and mitotic catastrophe induced by oxaliplatin and/or paclitaxel. RESULTS: Oxaliplatin at its IC(50) induced apoptosis and cell cycle arrest at G(2)-M phase. Western blot analyses indicated that oxaliplatin decreased mitosis-commencing protein cdc2 and anti-apoptotic proteins, phospho-Bcl(2) and Bcl-xl in the three colon cancer cells tested. Since cdc2 stabilizes survivin, a putative IAP (inhibitor of apoptosis) family member, through phosphorylation of Thr34, we examined the level of survivin and found a marked decrease due to oxaliplatin. This finding is of particular interest because survivin is a promising molecular target against various human cancers and a key molecule involved in both apoptosis and mitotic catastrophe. When used in combination with paclitaxel (taxol), a putative apoptosis-inducing reagent, the isobologram indicated that the taxol-oxaliplatin sequence or taxol plus oxaliplatin had synergic or additive effects, while the oxaliplatin-taxol sequence resulted in a prominent antagonism. The taxol-oxaliplatin sequence caused marked growth inhibition of DLD1 and SW480 cells, possibly due to upregulation of apoptotic and non-apoptotic pathways, respectively. Morphological surveys indicated that the non-apoptotic process could be mitotic catastrophe. CONCLUSION: Our results suggest that oxaliplatin that potently inhibited survivin may exert outstanding cytotoxic effects when combined with certain chemoreagents through enhancement of apoptosis and mitotic catastrophe.

Antineoplastic Agents↗

PubMed2005

Changes over time in thymidine phosphorylase and dihydropyrimidine dehydrogenase when colon cancer samples are left at room temperature.

The changes over time in thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) were studied when colon cancer samples were left at room temperature. The TP levels and the TP/DPD ratio showed no changes over time in either the tumor or normal tissues. DPD levels increased over time in the normal tissues (P = 0.015), but showed no changes in the tumor tissues. When the DPD level in normal tissues is to be examined, the samples should be frozen as soon as possible. In all other cases, the ELISA results will not be affected if the samples are frozen within 6 h after collection.

Colon↗

PubMed2005

Fusion image of positron emission tomography and computed tomography for the diagnosis of local recurrence of rectal cancer.

BACKGROUND: The aim of this study was to evaluate the clinical and therapeutic value of digital fusion image (FI) of positron emission tomography (PET) using (18)F-fluorodeoxy glucose and computed tomography (CT) in patients who were suspected of having a local recurrence of rectal cancer. METHODS: Forty-two patients (32 men and 10 women; mean age, 61.4 years, range, 40-79 years) with a suspicion of local recurrence after curative resection of rectal cancer were prospectively recruited and underwent (18)F-fluorodeoxy glucose-PET and CT. The FI was reconstructed with a commercially available digital software program, T-B Fusion. Wilcoxon signed rank test was used to compare FI with CT alone or PET alone. RESULTS: FI yielded a correct diagnosis in 39 (93%) of 42 patients, whereas CT alone and PET alone did so in 33 (79%) and 37 (88%) patients, respectively. FI had better diagnostic accuracy than CT alone (P = .0138) and PET alone (P = .0156). Overall, FI altered patient management in 11 (26.2%) patients on the basis of additional information, including differentiation of the tumor from the postoperative scar in 6 patients, exact anatomical location in 3 patients, and both in 2 patients. CONCLUSIONS: FI has a potential clinical value in the treatment of suspected local recurrence of rectal cancer.

Adenocarcinoma↗

PubMed2005

A simple technique for performing laparoscopic purse-string suturing during circular stapling anastomosis.

An esophagojejunostomy using a circular stapler requires the fixing of an anvil at the esophageal stump. When this placement procedure is laparoscopically performed, purse-string suturing is difficult, and there is a risk of loosening when a conventional needle driver is used. We herein present a simple but effective technique for performing laparoscopic purse-string suturing of the esophageal stump using a semiautomatic suturing device called the Endostitch. Gastrointestinal anvil placement was laparoscopically performed for 10 patients who underwent an esophagojejunostomy following a total gastrectomy. After the lumen of the esophagus was expanded using bowel forceps, the Endostitch was used to place approximately 12 encircling purse-string sutures. An anvil was positioned with support of the esophageal wall at three points with forceps. The Endostitch was used for the ligation with a sufficient degree of tension applied by extracorporeally pulling the sutures through the abdominal wall. The time for placement of the anvil averaged approximately 8 min. The ring formation following anastomosis was favorable in all patients. As a result, we consider our technique to be simple but very effective.

Anastomosis, Surgical↗

PubMed2005

High incidence of thrombosis of the portal venous system after laparoscopic splenectomy: a prospective study with contrast-enhanced CT scan.

OBJECTIVE: The aims of this prospective study were to investigate the true incidence of portal or splenic vein thrombosis (PSVT) after elective laparoscopic splenectomy using contrast-enhanced computed tomography (CT) scan, and outcome of anticoagulant therapy for PSVT. SUMMARY BACKGROUND DATA: Although rare, thrombosis of the portal venous system is considered a possible cause of death after splenectomy. The reported incidence of ultrasonographically detected PSVT after elective open splenectomy ranges from 6.3% to 10%. METHODS: Twenty-two patients underwent laparoscopic splenectomy (LS group), and 21 patients underwent open splenectomy (OS group). Preoperative and postoperative helical CT with contrast were obtained in all patients, and the extent of thrombosis was investigated. Prothrombotic disorder was also determined. RESULTS: PSVT occurred in 12 (55%) patients of the LS group, but in only 4 (19%) of the OS group. The difference was significant (P = 0.03). Clinical symptoms appeared in 4 of the 12 LS patients. Thrombosis occurred in the intrahepatic portal vein (n = 9), extrahepatic portal vein (n = 2), mesenteric veins (n = 1), proximal splenic vein (n = 4), and distal splenic vein (n = 8). Prothrombotic disorder was diagnosed in 1 patient. Anticoagulant therapy was initiated once the diagnosis was established, and complete recanalization, except for distal splenic vein, was observed without any adverse event. Patients with splenomegaly were at high risk of PSVT. CONCLUSIONS: PSVT is a more frequent complication of laparoscopic splenectomy than previously reported but can be treated safely following early detection by CT with contrast.

Aged↗

PubMed2005

Role of p21waf1/cip1 in effects of oxaliplatin in colorectal cancer cells.

Clinical studies have shown that oxaliplatin, a novel platinum derivative, is a potent chemotherapeutic agent for colorectal cancer when combined with 5-fluorouracil and leucovorin. Although the toxic activity is based on covalent adducts between platinum and DNA, its actual biological behavior is mostly unknown. In an effort to explore the mechanism of tumor susceptibility to oxaliplatin, we examined the cytotoxic effects of oxaliplatin in colorectal cancer cell lines in reference to p53 gene status. Although p53 gene status did not clearly predict sensitivity to oxaliplatin, p53 wild-type cells including HCT116 were sensitive but HCT116 p53-/- were found to be resistant to oxaliplatin. Oxaliplatin caused strong p21waf1/cip1 induction and G0-G1 arrest in p53 wild-type cells, whereas cisplatin did not induce G0-G1 arrest. Assays using p53 wild but p21waf1/cip1 null HCT116 cells revealed that oxaliplatin did not show G0-G1 arrest and reduced growth-inhibitory effects, suggesting that p21waf1/cip1 may be a key element in oxaliplatin-treated p53 wild-type cells. Although HCT116 is DNA mismatch repair-deficient, a mismatch repair-proficient HCT116+ch3 cell line displayed similar responses with regard to p21waf1/cip1-mediated growth inhibition and G0-G1 arrest. In p53 mutant cells, on the other hand, oxaliplatin caused an abrupt transition from G1 to S phase and eventually resulted in G2-M arrest. This abrupt entry into S phase was associated with loss of the p21waf1/cip1 protein via proteasome-mediated degradation. These findings suggest that p21waf1/cip1 plays a role in oxaliplatin-mediated cell cycle and growth control in p53-dependent and -independent pathways.

Antineoplastic Agents↗